Microwave sensing for neurodegenerative diseases

The rapidly increasing rate of the ageing population has led to a higher rate in people suffering from neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, are characterised by the progressive loss of brain cells, which leads to a decline in a person’s cognitive abilities, and eventually leads to death. The alarming increase in people suffering from these diseases has created a global socioeconomic burden that affects caregivers, nurses, and family members, just as much as the patient themselves. Due to the critical nature of these diseases, it is paramount that systems and devices can detect and monitor neurodegenerative diseases as early as possible, so that the right treatment can be provided to hinder its progression. Existing technologies have provided key results in the detection and monitoring of neurodegenerative diseases. However, they are limited by their bulky size, high costs, and inconvenient or invasive approach. Meanwhile, microwave sensing technology has generated promising results in several medical applications, such as cancer and stroke detection. The ability to fabricate components easily and integrate them into a wearable prototype makes microwave sensing a promising non-invasive, cost-effective, and portable or wearable solution for medical diagnostics. This work proposes the use of microwave sensing as an inexpensive, non-invasive, reliable, accurate, efficient, and wearable tool for monitoring the progression of neurodegenerative diseases. For evaluation, models were created to emulate symptoms of Alzheimer’s disease to demonstrate the technology. It is observed that microwave sensing was able to detect brain atrophy and lateral ventricle enlargement with a minimum change of 5%. In addition, microwave sensing could non-invasively detect and image regions of the brain affected by Alzheimer’s disease pathology, providing a transformational and major improvement compared to PET scans that rely on biomarkers. Moreover, microwave sensing could detect Alzheimer’s disease at one of its earliest stages: mild cognitive impairment. This work provides a promising and transformative approach for wearable and non-invasive neurodegenerative disease monitoring

Structural Polymorphism in Tau Filaments: An Implication for Neurodegenerative Diseases

Tau filaments are the pathological hallmark of \u3e20 neurodegenerative diseases including Alzheimer\u27s disease, Pick\u27s disease, and progressive supranuclear palsy. In the adult human brain, six isoforms of tau are expressed that differ by presence or absence of the second of the four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half has four repeats (4R tau). Site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy was used to obtain structural insights into tau filaments. The studies showed that the filaments of 4R tau and 3R tau share a highly ordered core structure in the third repeat with parallel, in-register arrangement of beta-strands. This structure in 3R and 4R is conserved regardless of whether full-length isoforms (htau40 and htau23) or truncated constructs (K18 and K19) are used. When mixed, 3R tau and 4R tau coassembled into heterogeneous filaments. Hence, these findings indicate that there are at least three compositionally distinct types of filaments: homogeneous 3R tau, homogeneous 4R tau, and heterogeneous 3R/4R tau. In vitro experiments show that the seeded filament growth, a prerequisite for tau spreading in tissue culture and brain, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms whereas seeds of 4R tau can recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. Conformational studies at the molecular level of tau filaments were done using Double electron-electron resonance spectroscopy, which allows the determination of distances between pairs of spin labels. These studies revealed structural differences between filaments of 3R tau and 4R tau. Furthermore, they indicated that 4R tau assumed the conformation of 3R tau when templated on 3R tau seeds. Our measurements have also provided insights into the heterogeneity of tau filament structure. Conformational differences due to variation in filament composition and seeding properties of tau filaments have shown that they are structurally polymorphic in nature. This structural polymorphism of tau filaments has widespread implications in understanding and treatment of neurodegenerative diseases

Experimental and Analysis of Electromagnetic Characterization of Biological and Non-Biological Materials in Microwave, Millimeter-wave, and Terahertz Frequency Bands

The goal of this research is to characterize the electromagnetic properties of biological and non-biological materials at terahertz (THz), millimeter-wave, and microwave frequency bands. The biological specimens are measured using the THz imaging and spectroscopy system, whereas the non-biological materials are measured using the microwave and millimeter-wave free-space system. These facilities are located in the Engineering Research Center at the University of Arkansas. The THz imaging system (TPS 3000) uses a Ti-Sapphire laser directed on the photoconductive antennas to generate a THz time domain pulse. Upon using the Fourier Transform, the spectrum of the pulsed THz signal includes frequencies from 0.1 THz to 4 THz. On the other hand, the free space system uses a PNA network analyzer to produce a signal at frequencies ranging from 10 MHz to 110 GHz. For the biological specimens, the research focused on imaging the freshly excised breast tumors to detect the cancer on the margins using THz radiation. The tumor margin assessment depends on the THz contrast between cancer, collagen, and fat tissues in the tumor. Three models of breast tumors are investigated in this research: humans, mice (xenograft and transgenic), and Sprague Dawley rats. The results showed good differentiation between the cancerous and non-cancerous tissues in all three models. In addition, an excellent distinction was observed between cancer, collagen, and fat in the formalin-fixed paraffin-embedded (FFPE) block tissue with ~ 90-95% correlation with the pathology images. Furthermore, the FFPE ductal carcinoma in situ (DCIS) tumors are investigated, also using the THz imaging. The THz images of the DCIS samples are compared with those of the FFPE invasive ductal carcinoma (IDC) specimens. The results demonstrated that THz electric field reflection from the IDC were higher than that from the collagen, DCIS, and then the fat tissue region. Furthermore, a pilot study is conducted to investigate the effect of optical clearance (e.g., glycerol solution) on THz images of freshly excised tumors. The results showed that the glycerol reduced the absorption coefficients of pre-treated tissues compared with those of untreated tissues. For the non-biological materials, the research focuses on characterizing highly conductive non-magnetic radar absorbing materials (RAM) for the automotive industry. The ingredients of material components in the RAM samples are unrevealed under a non-disclosure agreement (NDA). The material characterization involves the extraction of the complex relative permittivity utilizing the transmission measurement data obtained at the K-band (18 GHz to 26.5 GHz) and the W-band (75 GHz to 110 GHz). The measurements are obtained using the free-space conical horn antenna system. A transmission line based extraction model is implemented, and the results are validated with the experimental measurements of the S-parameters. The maximum error reported between the measured and the calculated S-parameters was less than 1 dB. In conclusion, the THz imaging of breast cancer tumors presents a potential margin assessment of other solid tumors, and the microwave, millimeter-wave, and THz spectroscopy of materials demonstrate a potential application in the fifth and sixth generations of wireless communications

ENABLING INTERVENTIONAL MRI USING AN ULTRA-HIGH FIELD LOOPLESS ANTENNA

Interventional magnetic resonance imaging (iMRI) utilizes multi-functional capabilities of MRI, for targeting therapy and monitoring response. Up to recently, most of the iMRI procedures have been conducted at magnetic field strengths (B0) of 1.5T or lower. MRI at ultra-high B0 (UHF, B0≥3T) provides higher signal-to-noise ratio (SNR) that can be traded for better image resolution and/or shorter scan durations. This dissertation investigates the performance of the interventional loopless antenna at UHF and introduces new methods to enable UHF iMRI using interventional loopless antennae. First, a new MRI denoising method based on a spectral subtraction technique that can provide up to 45% of SNR improvement is introduced. While achievable SNR gains using post-processing methods are limited, the SNR of MRI is intrinsically improved by moving to higher B0. Here, the performance of a loopless antenna was tested at 7T. The results show that SNR increases quadratically with B0 (SNR~B02) up to 7T. The increased SNR of the loopless antenna at UHF enables MRI at sub-50µm in-plane resolutions. At UHF, excitation of tissue deep within the body becomes challenging due to the decreased penetration depth, and radiofrequency (RF) safety limitations when external coils are used. To overcome these problems, we used the loopless antenna for both transmitting the RF field, and receiving the MR signal from the tissue. Spatially selective B1-insensitive pulses were employed to improve the excitation homogeneity, providing a ~10cm FOV, which would be suitable for both device-tracking and localizing potential targets inside the body. Use of interventional devices in transmit and/or receive mode may elevate temperatures near the device above levels considered safe. To address this problem, we built a loopless antenna RF radiometer operating at 3T MRI frequency, 128MHz, to monitor the local temperature around the device. We investigated its performance inside bio-analogous phantoms and using electromagnetic and thermal numerical simulations. The radiometer was able to detect uniform temperature with an accuracy <0.3°C at 2 measurements/second, and estimate the peak 1g-averaged temperature rise within 0.4°C. The loopless antenna radiometer can be used to ensure safety of interventional procedures, without requiring any additional leads or sensors, or even MRI

【研究分野別】シーズ集 [英語版]

[英語版

The Largest Unethical Medical Experiment in Human History

This monograph describes the largest unethical medical experiment in human history: the implementation and operation of non-ionizing non-visible EMF radiation (hereafter called wireless radiation) infrastructure for communications, surveillance, weaponry, and other applications. It is unethical because it violates the key ethical medical experiment requirement for “informed consent” by the overwhelming majority of the participants. The monograph provides background on unethical medical research/experimentation, and frames the implementation of wireless radiation within that context. The monograph then identifies a wide spectrum of adverse effects of wireless radiation as reported in the premier biomedical literature for over seven decades. Even though many of these reported adverse effects are extremely severe, the true extent of their severity has been grossly underestimated. Most of the reported laboratory experiments that produced these effects are not reflective of the real-life environment in which wireless radiation operates. Many experiments do not include pulsing and modulation of the carrier signal, and most do not account for synergistic effects of other toxic stimuli acting in concert with the wireless radiation. These two additions greatly exacerbate the severity of the adverse effects from wireless radiation, and their neglect in current (and past) experimentation results in substantial under-estimation of the breadth and severity of adverse effects to be expected in a real-life situation. This lack of credible safety testing, combined with depriving the public of the opportunity to provide informed consent, contextualizes the wireless radiation infrastructure operation as an unethical medical experiment

Studies in Furobenzopyran Chemistry

A series of 3-acyl(thio)chromones has been prepared. These compounds were acetalised with a variety of diols, with p-TsOH catalysis, under azeotropic conditions, to give the corresponding 3-acyl(thio)chromone acetals. A new rearrangement accompanies the formation of acetals from 3-acetyl- or 3-benzoyl- chromone giving a 2-methyl- or 2-phenyl- 3-formylchromone acetal. The rearrangement is initiated by conjugate addition of the diol to the chromone ring. The C-2 lithio derivatives of 3-acyl(thio)chromone acetals are generated by treatment with lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide (LTMP) in THF at low temperature. The anions have been intercepted with a variety of electrophiles. It was found that metallation with LTMP proceeds more efficiently. A number of novel 3-acyl-2-(1-hydroxyalkyl)(thio)chromone acetals has been prepared by electrophilic trapping with aldehydes. Three novel self-condensation dimers were obtained from lithiations of 3-acyl(thio)chromone acetals; the structures of two were established by X-ray crystallography. Mechanisms for their formation are presented. Whilst C-2 lithiation of 2-(4-oxo-4H[1]benzopyran-3-yl)-1,3-dioxane with n-BuLi does occur, the reaction is complex and leads, ultimately, to a benzofuranone derivative. The structure and relative stereochemistry of this compound, which possesses two 1,4-disposed stereogenic centres, was established by X-ray crystallography. The reaction also provides another compound, derived from 1,2-addition of n-BuLi to 2-(4-oxo-4H[1]benzopyran-3-yl)-1,3-dioxane. Lithiation of 2-(hydroxymethyl)chromone with LTMP initiates reduction ofthe pyranone ring, probably via a Single Electron Transfer mechanism. Electrophilic trapping of the intermediate anion with CICO2Et proceeds in a regio- and diastereospecific manner. Unmasking of the acetal function in 3-acyl-2- (1-hydroxyalkyl)(thio)chromone acetals is facile (p-TsOH in toluene) and proceeds with concomitant cyclisation to give novel 9H-furo[3,4-b][l]benzo(thio)pyran-9-ones. Cycloaddition reactions of the furobenzo(thio)pyranones have been investigated. When 3-methyl-9H-furo[3,4)[1]benzopyran-9-onereacts with methyl propiolate a pincer Diels-Alder reaction prevails, to give an octacyclic 2:1 adduct with complete regio- and stereo- specificity. The stereochemistry was established as syn exo-endo by X-ray crystallography. Dimethyl acetylenedicarboxylate reacts with 3-(4-methylphenyl)-9H-furo[3,4-b][1]benzopyran -9-one to give a mixture of the 1:1 and the anti exo-exo 2:1 adducts. 3H,9H-Furo[3,4b[1]benzopyran-1,9-dione has been obtained via a tandem acylation-SnAr reaction of ethyl 2-fluorobenzoylacetate. Protolysis of dimethyl 1,4-dihydro-1,4-epoxy4-(4-methylphenyl)-9-oxo-9H-thioxanthene-2,3-dicarboxylate gives the expected 1-hydroxythioxanthone derivative. However, the analogous 1,4-epoxyxanthene underwent an unprecedented hydrolytic cycloreversion to dimethyl 2-(4-methylphenyl) furan-3,4-dicarboxylate and 4-hydroxycoumarin. The acylation of 3-pyrrolidinodihydrothiophenes with 2-fluorobenzoyl chloride has been investigated as an entry to the 9H-thieno[3,4-b]benzopyran-9-one system. An unexpected product, 2,4-bis(2-fluorobenzoyl)-3-pyrrolidino-2,5-dihydrothiophene is formed predominantly

New insights about the beneficial properties of yerba mate for human health

Os compostos fenólicos têm sido extensivamente pesquisados pela hipótese de suas inúmeras propriedades para a saúde, a maioria das quais relacionadas à sua capacidade antioxidante. A Erva Mate (EM), ou Ilex Paraguariensis, é uma planta nativa da América do Sul que parece ter capacidade antioxidante e propriedades estimulantes, principalmente devido à presença de componentes bioativos como compostos fenólicos (CFs) e metilxantinas. Vários estudos, por outro lado, revelam que a biodisponibilidade e a absorção de CFs de produtos alimentícios pelo corpo humano é muito baixa, e que uma variedade de fatores pode influenciar seu metabolismo, muitos dos quais são atualmente pouco compreendidos ou desconhecidos do comunidade científica. O presente trabalho visa estudar diferentes métodos de extração de compostos bioativos da EM, além de identificar e quantificar CFs encontrados nos extratos, a fim de propor soluções para aumentar as quantidades de compostos extraídos e sua biodisponibilidade, otimizando sua capacidade antioxidante. Ao estudar diferentes métodos de extração de compostos bioativos da EM, as condições ótimas de extração dos CFs e clorofilados foram em água a 80 oC e tempo de 60 minutos, obtendo valores de 48,3 mg GAE g-1 e 2,0 g clorofila g- 1, respectivamente. Vale ressaltar que todos os tratamentos foram capazes de extrair mais Chl b do que Chl a. Em termos de atividade antioxidante medida por DPPH e ABTS, a extração com solução de metanol separou um maior número de compostos com maior atividade; entretanto, não foi capaz de separar os compostos que protegiam a desoxirribose contra os radicais hidroxila; neste caso, as extrações com água forneceram 8 valores mais elevados para HRSA. Nosso estudo demonstra a separação de produtos químicos com características benéficas na temperatura em que o mate é normalmente consumido. A Extração Assistida por Micro-ondas (EAM) forneceu boas condições em termos de tempo e temperatura para separação de CFs e Chls, mas pesquisas adicionais são necessárias para determinar os melhores parâmetros de separação. Na análise de HPLC, uma variedade significativa de CFs (29 no total) foi obtida como resultado de cada método de extração e cerca de 16 a 18 compostos por extração, principalmente compostos de ácido cafeoilquínico e seus dímeros e uma infinidade de diferentes ácidos hidroxicinâmicos, como ácido ferúlico (AF), ácido p-cumárico (pCA) e ácido cafeico (CA) e seus derivados. O ácido cafeico, por exemplo, foi detectado em todos os extratos. Os flavonóis, por outro lado, foram obtidos na forma de rutina, kaempferol, quercetina e também como combinações com carboidratos como o Kaempferol rutinosídeo (329 - 340 nm, 29,2 - 29,4 min). Quando analisamos as quantidades totais de compostos encontrados nos diferentes métodos de extração podemos verificar que a Extração aquosa (EA) 15 minutos e EA 60 miutos não tiveram diferença significativa entre os teores, com quantidades totais de 7020 mg L-1 (14,04 mg g-1) e 6756 mg L-1 (13,51mg g-1), respectivamente. EA 30 minutos apresentou diferença significativa com uma quantidade total de 12275 mg L-1 (24,55 mg g-1). EAM 700 W e 1000 W apresentaram quantidades totais de 5811 mg L-1 (11,62 mg g-1) e 6793 mg L-1 (13,58 mg g-1) e Extração por Solvente Metanol (ESM) apresentou uma quantidade total significativamente diferente de 25739 mg L- 1 (51,47 mg g-1), embora esses valores possam não ser replicáveis, pois os consumidores fazem suas próprias extrações com água e nunca com metanol. Os ácidos cafeoilquínicos foram os principais constituintes da fração fenólica do YM, representando mais de 50% de todos os fenólicos.Phenolic compounds have been extensively researched by hypothesis of their numerous health properties, the majority of which are related to their antioxidant capacity. Yerba Mate (YM), or Ilex Paraguariensis, is a South American native plant that seems to have antioxidant ability and stimulant properties, particularly due to the presence of bioactive components such as phenolic compounds (PCs) and methylxanthines. Several studies, on the other hand, reveal that the bioavailability and absorption of PCs from food products by the human body is very low, and that a variety of factors may influence their metabolism, many of which are currently little understood or unknown to the scientific community. The present work aims to study different methods of extraction of bioactive compounds from YM, in addition to identifying and quantifying PCs found in the extracts, in order to propose solutions to increase the amounts of extracted compounds and their bioavailability, optimizing their antioxidant capacity. When studying different extraction methods of bioactive compounds of YM, the optimum extraction conditions for phenolic and chlorophyll (Chl) components were in water at 80 oC and time of 60 minutes, obtaining values of 48.3 mg GAE g-1 and 2.0 g chlorophyll g-1, respectively. It is noteworthy that all treatments were able to extract more Chl b than Chl a. In terms of antioxidant activity measured by DPPH and ABTS, the methanol solution extraction separated a greater number of compounds with higher activity; however, it was unable to separate compounds that protected deoxyribose against hydroxyl radicals; in this case, water extractions yielded higher values for HRSA. Our study demonstrates the separation of chemicals with beneficial characteristics at the temperature at which mate is typically consumed. Microwave Assisted Extraction (MAE) provided good conditions in terms of time and temperature for separation of phenolic and Chls compounds, but additional research is needed to determine the best separation parameters. In the HPLC analysis, a significant variety of PCs (29 total) were obtained as a result of each extraction method and around 16 to 18 compounds for extraction, mainly composed of caffeoylquinic acid and its dimers and a multitude of different hydroxycinnamic acids, such as ferulic acid (FA), p-coumaric acid (pCA) and caffeic acid (CA) and its derivatives. Caffeic acid, for example, was detected in all extracts. Flavonols, on the other hand, were obtained in the form of rutin, kaempferol, quercetin and also as combinations with carbohydrates such as Kaempferol rutinoside (329 - 340 nm, 29.2 - 29.4 min). When we analyze the total amounts of compounds found in the different extraction methods we can verify that 7 Aqueous Extraction (AE) 15 minutes and AE 60 minutes had no significant difference between the contents, with total amounts of 7020 mg L-1 (14,04 mg g-1) and 6756 mg L-1 (13,51mg g-1), respectively. AE 30 minutes showed a significant difference with a total amount of 12275 mg L-1 (24,55 mg g-1). MAE 700 W and 1000 W showed total amounts of 5811 mg L-1 (11,62 mg g-1) and 6793 mg L-1 (13,58 mg g-1) and Methanol Solvent Extraction (MSE) presented a significant different total amount of 25739 mg L-1 (51,47 mg g-1), even though those values may not be replicable since consumers make their own extractions with water and never with methanol. Caffeoylquinic acids were the major constituents of the phenolic fraction of YM, representing more than 50% of all phenolics. In particular, 2-caffeoylquinic acid was the major compound in all extracts, followed by caffeoylquinic acid dimer and 4-caffeoylquinic acids. Em particular, o ácido 2-cafeoilquínico foi o composto majoritário em todos os extratos, seguido pelo dímero do ácido cafeoilquínico e pelos ácidos 4-cafeoilquínicos